Research supported by this grant has resulted in the identification of the membrane protein CD36 as an important facilitator of long-chain fatty acid uptake by several key metabolic tissues such as muscle and heart. In the last funding period, we have established the important physiological role of CD36 and documented how alterations in its expression level lead to abnormalities in the metabolism of both fatty acids and glucose. It was also shown that both CD36 deficiency and overexpression can modulate insulin sensitivity and the metabolic response to the diet. In the next funding period, our first objective will be to use the various animal models now available with genetically altered CD36 levels to gain a better understanding of the interaction between the metabolisms of fatty acids and glucose and on how this impacts susceptibility to insulin resistance. We will explore the molecular mechanisms that underlie some of these interactions. Our second objective is to examine the role of CD36 in the cross talk between adipose and muscle tissues by asking whether CD36 regulation plays a primary role in mediating the peripheral effects of leptin and ACRP30. These substances are released by adipose tissue to act on fatty acid oxidation by muscle and we postulate that they acutely and chronically regulate muscle CD36 levels. Our final objective is to determine the major factors that regulate fatty acid transport and CD36 membrane localization/function in muscle cells. The work proposed has physiological and potentially clinical significance. In humans, CD36 deficiency is as high as 18% in some subpopulations and it may be an important factor in the metabolic adaptation to diet and in susceptibility to some forms of diet-induced pathology. [unreadable] [unreadable]